Cancer Res Treat.  2017 Jan;49(1):219-229. 10.4143/crt.2016.190.

Anti-cancer Effects of a Novel Quinoline Derivative 83b1 on Human Esophageal Squamous Cell Carcinoma through Down-Regulation of COX-2 mRNA and PGEâ‚‚

• Pun IH
• Chan D
• Chan SH
• Chung PY
• Zhou YY
• Law S
• Lam AK
• Chui CH
• Chan AS
• Lam KH
• Tang JC

• KMID: 2367520
• DOI: http://doi.org/10.4143/crt.2016.190

Abstract

PURPOSE
83b1 is a novel quinoline derivative that has been shown to inhibit cancer growth in human esophageal squamous cell carcinoma (ESCC). This study was conducted to comprehensively evaluate the cytotoxic effects of 83b1 on a series of ESCC cell lines and investigate the mechanisms by which 83b1 suppresses cancer growth based on molecular docking analysis.
MATERIALS AND METHODS
A series of ESCC and nontumor immortalized cell lines were exposed to 83b1 and cisplatin (CDDP) in a dose-dependent manner, and the cytotoxicity was examined by a MTS assay kit. Prediction of the molecular targets of 83b1 was conducted by molecular docking analysis. Expression of cyclooxygenase 2 (COX-2) mRNA and COX-2-derived prostaglandin Eâ‚‚ (PGEâ‚‚) were measured by quantitative real-time polymerase chain reaction and enzymelinked immuno-sorbent assay, respectively. In vivo anti-tumor effect was determined using a nude mice xenografted model transplanted with an ESCC cell line, KYSE-450.
RESULTS
83b1 showed the significant anti-cancer effects on all ESCC cell lines compared to CDDP; however, 83b1 revealed much lower toxic effects on non-tumor cell lines than CDDP. The predicted molecular target of 83b1 is peroxisome proliferator-activated receptor delta (PPARδ), which is a widely known oncoprotein. Additionally the expression of COX-2 mRNA and COX-2-derived PGE2 were down-regulated by 83b1 in a dose-dependent manner in ESCC cell lines. Furthermore, 83b1 was shown to significantly reduce the tumor size in nude mice xenograft.
CONCLUSION
The results of this study suggest that the potential anti-cancer effects of 83b1 on human esophageal cancers occur through the possible oncotarget, PPARδ, and down-regulation of the cancer related genes and molecules.

Keyword

Quinolines; Esophageal squamous cell carcinoma; PPAR delta; Cyclooxygenase 2; Dinoprostone; Cell cytotoxicity; Reverse transcription polymerase chain reaction; Real-time polymerase chain reaction; Nude-mice; Heterografts

MeSH Terms

Animals
Carcinoma, Squamous Cell*
Cell Line
Cisplatin
Cyclooxygenase 2
Dinoprostone
Down-Regulation*
Epithelial Cells*
Esophageal Neoplasms
Heterografts
Humans*
Mice
Mice, Nude
Molecular Docking Simulation
PPAR delta
Quinolines
Real-Time Polymerase Chain Reaction
RNA, Messenger*
Cisplatin
Cyclooxygenase 2
Dinoprostone
PPAR delta
Quinolines
RNA, Messenger

Figure

• 

  Fig. 1. Structure of 4-hydroxy-6-methoxyquinoline-2-carboxylic acid.

• 

  Fig. 2. Structure of 83b1.

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  Fig. 3. (A-I) Inhibitory effects of 83b1 on ESCC and non-tumor cell lines examined by MTS cytotoxicity assay. ESCC, esophageal squamous cell carcinoma; MTS, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium.

• 

  Fig. 4. Molecular docking of 83b1 (A) and arachidonic acid (B) on peroxisome proliferator-activated receptor δ.

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  Fig. 5. The down-regulating effects of 83b1 on cyclooxygenase 2 (COX-2) mRNA expression in KYSE-150 (A), KYSE-450 (B), SLMT-1 (C), and HKESC-4 (D). DMSO, dimethylsulfoxide. *p < 0.05, **p < 0.01, and ***p < 0.001 vs. untreated control, n=4.

• 

  Fig. 6. The down-regulating effects of 83b1 on prostaglandin E2 (PGE2) production in KYSE-150 (A), KYSE-450 (B), and SLMT-1 (C). **p < 0.01, ***p < 0.001 vs. untreated control, n=4.

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  Fig. 7. Tumor xenografts in athymic nude mice derived from KYSE-450 were treated with 10 mg/kg/day of 83b1 or 6% polyethylene glycol (PEG) control through intraperitoneal injection. 83b1 significantly reduced the tumor volume on the 19th day. ***p < 0.001 vs. control, n=5.

Reference

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